Classical Hodgkin lymphoma (cHL) is a B-cell malignancy diagnosed in approximately 20,000 new patients in North America and Europe each year; over 90% of these patients are young adults. Classical HLs include small numbers of malignant Reed-Sternberg (RS) cells within an extensive inflammatory infiltrate (Re et al. (2005) J Clin Oncol 23:6379-6386) which includes abundant T helper (Th)-2 and T regulatory (Treg) cells. The tumor cells derive from pre-apoptotic germinal center B cells that have undergone crippling mutations of their rearranged immunoglobulin genes (Re et al. (2005) J Clin Oncol 23:6379-6386; Kanzler et al. (1996) J Exp Med 184:1495-1505). Classical HL RS cells lack B-cell receptor-mediated signals and rely on alternative survival and proliferation pathways activated by transcription factors such as NF-κB and AP1 (Mathas et al. (2002) EMBO J. 21: 4104-4113; Kuppers et al. (2002) Ann Oncol 13:11-18; Schwering et al. (2003) Blood 101:1505-1512). In cHL, the tumor cells exhibit constitutive AP1 activation, express high levels of the AP1 components, cJUN and JUNB, and depend upon AP1-mediated proliferation signals (Mathas et al. (2002) EMBO J. 21: 4104-4113).
Although primary cHLs have a brisk inflammatory infiltrate, there is little evidence of an effective host anti-tumor immune response. The reactive T-cell population includes predominantly Th2-type and CD4+ CD25high FOXP3+ Treg cells that directly suppress immune responses and protect cHL RS cells from immune attack (Re et al. (2005) J Clin Oncol 23:6379-6386; Marshall et al. (2004) Blood 103:1755-1762; Gandhi et al. (2006) Blood 108:2280-2289, Ishida et al. (2006) Cancer Res 66:5716-5722); Th1, NK and cytotoxic T cells are markedly under-represented. In addition, primary cHLs are characterized by a unique cytokine and chemokine profile, including IL-4, IL-5, IL-10 and IL-13 (Re et al. (2005) J Clin Oncol 23:6379-6386; Skinnider et al. (2002) Leuk Lymphoma 43:1203-1210). In fact, IL-13 is a critical growth factor for cHL RS cells (Re et al. (2005) J Clin Oncol 23:6379-6386; Skinnider et al. (2002) Leuk Lymphoma 43:1203-1210). However, the molecular signals and endogenous factors responsible for creating and maintaining the Th2-skewed immunosuppressive microenvironment in cHL remain to be defined.
Galectins have recently emerged as novel regulators of immune cell homeostasis, and tumor immune escape (Rabinovich et al. (2002) Trends Immunol 23:313-320; Liu and Rabinovich (2005) Nature Reviews Cancer 5:29-41; Rubinstein et al. (2004) Cancer Cell 5:241-251; Le et al. (2005) J Clin Oncol 23:8932-8941). Galectin-1 (Gal1), an evolutionarily conserved member of this family (Vasta et al. (2004) Curr Opin Struct Biol 14:617-630), preferentially recognizes multiple Gal β1,4 GlcNAc (LacNAc) units which may be presented on the branches of N- or O-linked glycans on cell surface glycoproteins such as CD45, CD43 and CD7 (Stillman et al. (2006) J Immunol 176:778-789). Through binding and crosslinking of specific glycoconjugates, Gal1 has the potential to inhibit T-cell effector functions and regulate the inflammatory response (Perillo et al. (1995) Nature 378:736-739; Rabinovich et al. (1999) J Exp Med 190:385-397; Toscano et al. (2006) J Immunol 176:6323-6332; Santucci et al. (2003) Gastroenterol 124: 1381-1394; Baum et al. (2003) Clin Immunol 109:295-307). In several murine models of chronic inflammatory diseases, recombinant Gal1 suppressed Th1-dependent responses and increased T-cell susceptibility to activation-induced cell death (Rabinovich et al. (1999) J Exp Med 190:385-397; Toscano et al. (2006) J Immunol 176:6323-6332; Santucci et al. (2003) Gastroenterol 124: 1381-1394; Baum et al. (2003) Clin Immunol 109:295-307).
In a recently described solid tumor (murine melanoma) model, Gal1 was also found to play a pivotal role in promoting escape from T-cell-dependent immunity and conferring immune privilege to tumor cells (Rubinstein et al. (2004) Cancer Cell 5:241-251). In this model, Gal1 blockade markedly enhanced syngeneic tumor rejection and tumor-specific T-cell-mediated immune responses (Rubinstein et al. (2004) Cancer Cell 5:241-251). In another recently described solid tumor (head and neck squamous cell carcinomas), Gal1 overexpression was inversely correlated with the number of infiltrating T cells and was an independent prognostic factor for shorter overall survival (Le et al. (2005) J Clin Oncol 23:8932-8941). WO2006/108474 describes the use of RNAi molecules for the treatment of cancer and non-Hodgkin's lymphoma.
In view of the above, it is clear that there remains a need in the art for compositions and methods to combat immune disorders, including Hodgkin lymphoma. The present invention relates in general to a role of Gal1 in immune disorders, including Hodgkin lymphoma.